Dataset Information

Altered splenic [89Zr]Zr-rituximab uptake in patients with interstitial lung disease not responding to rituximab: could this indicate a splenic immune-mediated mechanism?

ABSTRACT: Rituximab (RTX) for immune-mediated inflammatory disease (IMID) with interstitial pneumonitis (IP) results in non-response in about a third of patients for reasons not well understood. Complete peripheral B-cell depletion in IMID-IP does not seem to correlate with successful treatment outcome. A hypothesis is that splenic B cells might play a role in B-cell recovery and attraction of naïve B cells in non-responsive patients. The aim of this post hoc analysis of clinical trial data is to search for indicators in [89Zr]Zr-rituximab PET/CT data from the spleen that might explain non-responsiveness. PET/CT data of 20 patients with IMID-IP, who were enrolled in a phase II trial and treated with RTX were analyzed. Clinical outcome was categorized into responders (RSP) and non-responders (NR) after 6 months of initial RTX by two independent pulmonologists. Patients were examined separately to search for associations between clinical outcome, splenic activity on PET/CT, lymphocyte counts and other biomarkers. Treatment failure was found in 6/20 patients (30%) while all patients exhibited B-cell depletion from the circulation. NR patients demonstrated significantly higher splenic activity than RSP patients (non-preload protocol: SUV 4.9±1.96 and SUV 2.3±1.08 respectively, P=0.025). No correlations between treatment outcome and serum lymphocyte subsets were found. Our findings suggest a potential splenic mechanism in IMID-IP patients non-responding to RTX and warrant further consideration and investigation.

SUBMITTER: Adams H

PROVIDER: S-EPMC7486548 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Altered splenic [<sup>89</sup>Zr]Zr-rituximab uptake in patients with interstitial lung disease not responding to rituximab: could this indicate a splenic immune-mediated mechanism?

Adams Human H Meek Bob B van de Garde Ewoudt Mw EM van Moorsel Coline Hm CH Vugts Danielle J DJ Keijsers Ruth G RG Grutters Jan C JC

American journal of nuclear medicine and molecular imaging 20200825 4

Rituximab (RTX) for immune-mediated inflammatory disease (IMID) with interstitial pneumonitis (IP) results in non-response in about a third of patients for reasons not well understood. Complete peripheral B-cell depletion in IMID-IP does not seem to correlate with successful treatment outcome. A hypothesis is that splenic B cells might play a role in B-cell recovery and attraction of naïve B cells in non-responsive patients. The aim of this post hoc analysis of clinical trial data is to search f ...[more]

PMID: 32929395

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Project description:BackgroundIn vivo monitoring of cell biodistribution using positron emission tomography (PET) provides a quantitative non-invasive method to further optimize cell therapies and related new developments in the field. Our group has earlier optimized and evaluated the in vitro properties of two radiotracers,[89Zr]Zr-(oxinate)4 and [89Zr]Zr-DFO-NCS, for the radiolabelling of different cell types. Here, we performed a microPET study to assess the in vivo biodistribution of cells in rats using these two radiotracers. Human decidual stromal cells (hDSC) and rat macrophages (rMac) were radiolabelled with [89Zr]Zr-(oxinate)4 or [89Zr]Zr-DFO-NCS. Rats were intravenously injected with radiolabelled cells, and the in vivo biodistribution was monitored with microPET/CT imaging for up to day 7. Organ uptake was evaluated and presented as a percentage of injected activity per gram tissue (%IA/g) and total absorbed organ doses (mSv/MBq).ResultsThe biodistribution in vivo showed an immediate uptake in the lungs. Thereafter, [89Zr]Zr-(oxinate)4 labelled cells migrated to the liver, while the signal from [89Zr]Zr-DFO-NCS labelled cells lingered in the lungs. The differences in the in vivo behaviour for the same cell type appeared related to the radiotracer labelling. After 24 h, [89Zr]Zr-(oxinate)4 labelled cells had over 70% higher liver uptake for both hDSC and rMac compared to [89Zr]Zr-DFO-NCS labelled cells, whereas [89Zr]Zr-DFO-NCS labelled cells showed over 60% higher uptake in the lungs compared to [89Zr]Zr-(oxinate)4 labelled cells. This difference in both lung and liver uptake continued until day 7. Dosimetry calculations showed a higher effective dose (mSv/MBq) for [89Zr]Zr-DFO-NCS compared to [89Zr]Zr-(oxinate)4, for both cell types. Although the bone uptake was higher for [89Zr]Zr-(oxinate)4 labelled cells, the prolonged uptake in the lungs contributed to a significant crossfire to bone marrow resulting in a higher bone dose.ConclusionThe [89Zr]Zr-DFO-NCS labelled cells suggest a prolonged accumulation in the lungs, while [89Zr]Zr-(oxinate)4 suggests quicker clearance of the lungs followed by accumulation in the liver. Accumulation of radiolabelled cells in the liver corresponds to other cell-tracking methods. Further studies are required to determine the actual location of the [89Zr]Zr-DFO-NCS labelled cell.

Project description:BackgroundThere is a need to better characterise cell-based therapies in preclinical models to help facilitate their translation to humans. Long-term high-resolution tracking of the cells in vivo is often impossible due to unreliable methods. Radiolabelling of cells has the advantage of being able to reveal cellular kinetics in vivo over time. This study aimed to optimise the synthesis of the radiotracers [89Zr]Zr-oxine (8-hydroxyquinoline) and [89Zr]Zr-DFO-NCS (p-SCN-Bn-Deferoxamine) and to perform a direct comparison of the cell labelling efficiency using these radiotracers.ProceduresSeveral parameters, such as buffers, pH, labelling time and temperature, were investigated to optimise the synthesis of [89Zr]Zr-oxine and [89Zr]Zr-DFO-NCS in order to reach a radiochemical conversion (RCC) of >95 % without purification. Radio-instant thin-layer chromatography (iTLC) and radio high-performance liquid chromatography (radio-HPLC) were used to determine the RCC. Cells were labelled with [89Zr]Zr-oxine or [89Zr]Zr-DFO-NCS. The cellular retention of 89Zr and the labelling impact was determined by analysing the cellular functions, such as viability, proliferation, phagocytotic ability and phenotypic immunostaining.ResultsThe optimised synthesis of [89Zr]Zr-oxine and [89Zr]Zr-DFO-NCS resulted in straightforward protocols not requiring additional purification. [89Zr]Zr-oxine and [89Zr]Zr-DFO-NCS were synthesised with an average RCC of 98.4 % (n = 16) and 98.0 % (n = 13), respectively. Cell labelling efficiencies were 63.9 % (n = 35) and 70.2 % (n = 30), respectively. 89Zr labelling neither significantly affected the cell viability (cell viability loss was in the range of 1-8 % compared to its corresponding non-labelled cells, P value > 0.05) nor the cells' proliferation rate. The phenotype of human decidual stromal cells (hDSC) and phagocytic function of rat bone-marrow-derived macrophages (rMac) was somewhat affected by radiolabelling.ConclusionsOur study demonstrates that [89Zr]Zr-oxine and [89Zr]Zr-DFO-NCS are equally effective in cell labelling. However, [89Zr]Zr-oxine was superior to [89Zr]Zr-DFO-NCS with regard to long-term stability, cellular retention, minimal variation between cell types and cell labelling efficiency.

Dataset Information

Altered splenic [89Zr]Zr-rituximab uptake in patients with interstitial lung disease not responding to rituximab: could this indicate a splenic immune-mediated mechanism?

Publications

Altered splenic [<sup>89</sup>Zr]Zr-rituximab uptake in patients with interstitial lung disease not responding to rituximab: could this indicate a splenic immune-mediated mechanism?

Similar Datasets

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